This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prevalence of obesity in the United States has led to a significant increase in the complications associated with diabetes and cardiovascular disease known as metabolic syndrome. The metabolic syndrome represents a specific clustering of cardiovascular risk factors in the same individual (abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance, a prothrombotic state, and a proinflammatory state) with African-American women 60 percent more likely than African-American men to have the syndrome. Recent studies have revealed that monocytes and macrophages play a pivotal role in the development of obesity-induced inflammation. Each of these cell populations elaborates proinflammatory, pro-coagulant and acute phase proteins implicated in obesity-induced complications. Macrophages accumulate in adipose tissue in proportion to adiposity in both rodents and humans, and obesity increases the number of circulating monocytes. However, the link between inflammation and metabolic syndrome is not fully understood. Macrophage phagocytosis and migration, cytokine production, level of activation, and state of differentiation have been shown to be regulated by specific potassium K+ ionic current activity. K+ channels play pivotal roles in maintenance of the resting membrane potential, regulation of the action potential duration, receptor-dependent inhibition of cellular excitability, and the secretion and absorption of K+ ions across cell membrane. Our work provides evidence that long-lived macrophages at the sites of inflammation are likely to have a modified K+ current profile that would enhance macrophage function. We will test the hypothesis that altered ion transport mechanisms enhance macrophage function and contribute to the increased predisposition of obese African American women for developing diabetes mellitus and cardiovascular disease. The Specific Aims described below are formulated to test this central hypothesis. Specific Aim 1: Define the contribution of enhanced levels of oxidative stress, adipokine production and foam cell formation to the relationship between adiposity (lean versus obese) and pro-inflammatory status of obese African American women with metabolic syndrome. Specific Aim 2: Characterize the K+ channel species underlying K+ currents in macrophages from lean or obese African American women with metabolic syndrome and their impact on oxidative burst activity, adipokine production and foam cell formation. Progress to Date on project: A. Specific Aims Specific Aim 1: Define the contribution of enhanced levels of oxidative stress, cytokine production and foam cell formation to the relationship between adiposity (lean versus obese) and pro-inflammatory status of obese African American women with metabolic syndrome. Specific Aim 2: Characterize the K+ channel species underlying K+ currents in macrophages from lean or obese African American (AA) women with metabolic syndrome and their impact on oxidative burst activity, cytokine production and foam cell formation. B. Studies and Results Specific Aim 1: Lean and Obese African American Macrophages